Search

The potential benefit of heart rate reduction (HRR), independent of β-blockade, on right ventricular (RV) function in pulmonary hypertension (PH) remains undecided. We studied HRR effects on RV fib...

Right ventricular (RV) dysfunction determines mortality in patients with pulmonary arterial hypertension (PAH) and RV pressure loading. Experimental models commonly use Sugen hypoxia (SuHx)-induced PAH, monocrotaline (MCT)-induced PAH, or pulmonary artery banding (PAB). Because PAH models cannot interrogate RV effects or therapies independent of pulmonary vascular effects, we aimed to compare RV function and fibrosis in experimental PAB vs. PAH. Thirty rats were randomized to either sham controls, PAB, SuHx-, or MCT-induced PAH. RV pressures and function were assessed by high-fidelity pressure-tipped catheters and by echocardiography. RV myocyte hypertrophy, fibrosis, and capillary density were quantified from hematoxylin-eosin, picrosirius red-stained, and CD31-immunostained RV sections, respectively. RV pressures and the RV-to-left ventricular pressure ratio were significantly increased in all three groups to a similar degree (PAB 65 ± 17 mmHg, SuHx 72 ± 16 mmHg, and MCT 70 ± 12 mmHg) vs. controls (23 ± 2 mmHg, all

As the important role of longitudinal shortening in ventricular function has been well recognized over the past decade, evaluation of longitudinal systolic function of the left ventricle has become a subject of growing interest. Tissue motion annular displacement of the mitral valve (TMAD) is a new parameter of longitudinal systolic function. Although some studies have reported that this new parameter correlates with left ventricular ejection fraction (LVEF) in adults, little is known about TMAD in normal children. In this work, we investigated 94 children with no history of cardiovascular disease. TMAD was measured in the apical four-chamber view using the two-dimensional speckle tracking technique. Three points for tracking were selected in a diastolic frame: the lateral mitral valve annulus, medial mitral valve annulus, and left ventricular apex. The value was expressed as the percentage of displacement of the midpoint of the mitral valve annulus, using software to correct for left ventricular length at end-diastole. Pearson’s coefficient was used to estimate the correlation between TMAD and left ventricular systolic function parameters including the biplane modified Simpson method-derived ejection fraction and global longitudinal strain (GLS). We also analyzed the correlation between TMAD and heart rate (HR), height, age, and body surface area (BSA). TMAD was found to correlate significantly with LVEF (r = 0.71, p

Background Development of right ventricular ( RV ) hypertension eventually contributes to RV and left ventricular ( LV ) myocardial fibrosis and dysfunction. The molecular mechanisms are not fully elucidated. Methods and Results Pulmonary artery banding was used to induce RV hypertension in rats in vivo. Then, we evaluated cardiac function and regional remodeling 6 weeks after pulmonary artery banding. To further elucidate mechanisms responsible for regional cardiac remodeling, we also mimicked RV hypertensive stress by cyclic mechanical stretching applied to confluent cultures of cardiac fibroblasts, isolated from the RV free wall, septal hinge points, and LV free wall. Echocardiography and catheter evaluation demonstrated that rats in the pulmonary artery banding group developed RV hypertension with leftward septal displacement, LV compression, and increased LV end‐diastolic pressures. Picrosirius red staining indicated that pulmonary artery banding induced marked RV fibrosis and dysfunction, with prominent fibrosis and elastin deposition at the septal hinge points but less LV fibrosis. These changes were associated with proportionally increased expressions of integrin‐β1 and profibrotic signaling proteins, including phosphorylated Smad2/3 and transforming growth factor‐β1. Moreover, mechanically stretched fibroblasts also expressed significantly increased levels of α‐smooth muscle actin, integrin‐β1, transforming growth factor‐β1, collagen I deposition, and wrinkle formation on gel assays, consistent with myofibroblast transformation. These changes were not observed in parallel cultures of mechanically stretched fibroblasts, preincubated with the integrin inhibitor ( BTT ‐3033). Conclusions Experimentally induced RV hypertension triggers regional RV , hinge‐point, and LV integrin β1‐dependent mechanotransduction signaling pathways that eventually trigger myocardial fibrosis via transforming growth factor‐β1 signaling. Reduced LV fibrosis and preserved global function, despite geometrical and pressure aberrations, suggest a possible elastin‐mediated protective mechanism at the septal hinge points.

IMPORTANCE: Few studies with sufficient statistical power have shown the association of the z score of the coronary arterial internal diameter with coronary events (CE) in patients with Kawasaki disease (KD) with coronary artery aneurysms (CAA). OBJECTIVE: To clarify the association of the z score with time-dependent CE occurrence in patients with KD with CAA. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, collaborative retrospective cohort study of 44 participating institutions included 1006 patients with KD younger than 19 years who received a coronary angiography between 1992 and 2011. MAIN OUTCOMES AND MEASURES: The time-dependent occurrence of CE, including thrombosis, stenosis, obstruction, acute ischemic events, and coronary interventions, was analyzed for small (z score

The objective of the present study was to investigate mechanisms of heart rate (HR) reduction on biventricular function and interactions in experimental pulmonary arterial hypertension (PAH). We compared cardiac cycle mechanics and interventricular interactions in 15 sham, 8 monocrotaline-PAH, 9 PAH + carvedilol, and 8 PAH + ivabradine rats. We used echocardiography to assess biventricular function, timing of cardiac cycle events, and septal position in PAH rats and related HR reduction effects on biventricular function measured by echocardiography and conductance catheter. HR was 302 beats/min in PAH + carvedilol rats and 303 beats/min in PAH + ivabradine rats versus 359 beats/min in PAH rats ( P < 0.01). Sham rats showed temporal alignment between right ventricular (RV) and left ventricular (LV) events, whereas PAH rats showed increased biventricular isovolumic contraction times (ICTs), delayed RV peak radial motion, and impaired early relaxation. Temporal malalignment was associated with decreased tricuspid and mitral diastolic annular peak velocities (3.7 vs. 6.4 and 3.4 vs. 5.3 cm/s, respectively, P < 0.001), delayed and shortened biventricular filling, and reduced early diastolic LV filling velocity (0.56 vs. 0.81 cm/s, P < 0.01). LV eccentricity index was increased at systole (2.0 vs. 1.2, P < 0.001), early diastole (2.1 vs. 1.1, P < 0.001), and end diastole (1.6 vs. 1.1, P < 0.001) in PAH versus sham rats. HR reduction with carvedilol and ivabradine shortened biventricular ICTs and the time to biventricular peak radial motion, improved RV relaxation, and increased early diastolic LV filling through reduced interventricular interaction and improved timing. These improvements corresponded with enhanced hemodynamics (increased cardiac output, RV contractility, and diastolic relaxation). In conclusion, HR reduction by carvedilol and ivabradine improves biventricular filling and hemodynamics in experimental PAH through realignment of RV-LV cardiac cycle events and improved interventricular interactions. NEW & NOTEWORTHY Carvedilol improves biventricular function in experimental pulmonary arterial hypertension, but the mechanisms of heart rate reduction versus β-blocker effect are inadequately defined. Here, we demonstrate that reducing heart rate using either carvedilol or ivabradine (hyperpolarization-activated current inhibitor without β-blocker effect) improves right ventricular filling and biventricular hemodynamics through the realignment of right ventricular-left ventricular cardiac cycle events and improved interventricular interactions.

Death and morbidity in pulmonary arterial hypertension (PAH) are often due to right ventricular (RV) failure and associated left ventricular (LV) dysfunction. We investigated regional myocardial remodeling and function as the basis for adverse ventricular‐ventricular interactions in experimental chronic RV pressure overload. Two distinct animal models were studied: A rabbit model of increased RV pressure‐load through progressive pulmonary artery banding A rat model of monocrotaline (MCT)‐induced pulmonary arterial hypertension (PAH). Regional myocardial function was assessed by speckle‐tracking strain echocardiography and ventricular pressures measured by catheterization before termination. Regional RV and LV myocardium was analyzed for collagen content, apoptosis and pro‐fibrotic signaling gene and protein expression. Although the RV developed more fibrosis than the LV; in both models the LV was substantially affected. In both ventricles, particularly the LV, fibrosis developed predominantly at the septal hinge‐point regions in association with decreased regional and global circumferential strain, reduced global RV and LV function and up‐regulation of regional transforming growth factor‐β1 (TGF β1) and apoptosis signaling. A group of PAH rats who received the TGF β blocker SB431542 showed improved RV function and reduced regional hinge‐point myocardial fibrosis. RV pressure‐loading and PAH lead to biventricular TGF β1 signaling, fibrosis and apoptosis, predominantly at the septal hinge‐point regions, in association with regional myocardial dysfunction. This suggests that altered geometry and wall stress lead to adverse RV‐LV interactions through the septal hinge‐points to induce LV fibrosis and dysfunction.

Sildenafil is a strong pulmonary vasodilator that increases the intracellular cyclic guanosine monophosphate concentration through inhibition of phosphodiesterase-5. We assessed the benefit of oral sildenafil for persistent pulmonary hypertension early after congenital cardiac surgery in paediatric patients.Sildenafil was administered at a starting dose of 0.5 mg kg(-1) following admission to the intensive care unit. With careful monitoring of haemodynamics, the dose was increased stepwise by 0.5 mg kg(-1) every 4-6 h up to a maximum of 2 mg kg(-1). After successful weaning from a ventilator and from other vasodilators, sildenafil was gradually discontinued over the next 5-7 days.A retrospective review of medical records showed an age distribution of1 month (n=26),or = 1-6 months (n=36),or = 6-12 months (n=19), 1-3 years (n=8), 4-9 years (n=9) and10 years (n=2) at the time of surgery. The surgeries were performed for ventricular septal defect closure (n=17), arterial switch (n=30), truncus arteriosus repair (n=10), complete atrioventricular septal defect repair (n=12), total anomalous venous drainage repair (n=9), and other open-heart surgery (n=22). The aforementioned concomitant inhaled nitrous oxide treatment was performed in 66 patients. Pulmonary arterial pressure decreased in 28, was unchanged in five and elevated in one patient out of the total of 34 cases for which data from continuous pressure monitoring were available. Bosentan was added in three cases with persistent symptoms due to pulmonary hypertension despite sildenafil treatment. After sildenafil administration, modest oxygen desaturation occurred in seven cases, but no 'rebound' pulmonary hypertension occurred. There were no significant adverse events during sildenafil treatment.Our results suggest that oral sildenafil is a safe and effective alternate for persistent pulmonary hypertension following congenital heart surgery in children.

Background In muscular dystrophy, cardiac function deteriorates with time and heart failure is one of the major causes of death. Although the combination of angiotensin-converting enzyme inhibitors (ACEI) and β-blockers improves cardiac function in adults, little is known about the efficacy of those drugs in patients with muscular dystrophy. Methods and Results The effect of the β-blocker, carvedilol, and/or ACEI on ventricular function in patients with muscular dystrophy was studied. Carvedilol and an ACEI were given to 13 patients (ACEI group; mean age 18 years, range 7-27 years), and an ACEI only to 15 patients (carvedilol group; mean age 15 years, range 8-29 years). Diagnoses included Duchenne muscular dystrophy (n=25), Fukuyama muscular dystrophy (n=2), and Emery-Dreifuss muscular dystrophy (n=1). Echocardiographic parameters of the left ventricle were measured during the 2-3 years of follow-up. In the carvedilol group, combination therapy of carvedilol and an ACEI for 2 years resulted in a significant increase in left ventricular fractional shortening (LVFS). In the ACEI group, there was no significant change in LVFS. Left ventricular end-diastolic dimension increased in the ACEI group, but not in the carvedilol group. Conclusion Carvedilol plus an ACEI improves left ventricular systolic function in patients with muscular dystrophy. (Circ J 2006; 70: 991 - 994)

Left ventricular (LV) function influences outcomes in right ventricular (RV) failure. Carvedilol reduces mortality in LV failure and improves RV function in experimental pulmonary arterial hypertension (PAH). However, its impact on ventricular-ventricular interactions and LV function in RV afterload is unknown. We investigated effects of carvedilol on biventricular fibrosis and function in a rat model of persistent PAH. Rats were randomized into three groups: Sham controls, PAH, and PAH + carvedilol. Severe PAH was induced by 60 mg/kg subcutaneous monocrotaline. In the treatment group, oral carvedilol (15 mg/kg/day) was started 2 weeks after monocrotaline injection and continued for 3 weeks until the terminal experiment. Echocardiography and exercise performance were performed at baseline and repeated at the terminal experiment with hemodynamic measurements. LV and RV myocardium were analyzed for hypertrophy, fibrosis, and molecular signaling by protein and mRNA analysis. PAH and PAH + carvedilol rats experienced severely elevated pulmonary arterial pressures and RV hypertrophy. Despite similar RV systolic pressures, carvedilol reduced biventricular collagen content (RV fibrosis area; 13.4 ± 6.5 vs. 5.5 ± 2.7 %, p

Right ventricular (RV) function is an important determinant of mortality in patients with idiopathic pulmonary arterial hypertension (iPAH). The aim of this study was to serially evaluate global and regional RV two-dimensional strain and their relation to transplantation-free survival in children with iPAH.RV regional and global longitudinal strain was retrospectively assessed in children with iPAH. Serial echocardiograms at 3 to 6 months from presentation and then at yearly intervals were analyzed. Results were compared with those from controls and between iPAH survivors (group 1) and those who died or needed transplantation (group 2). Survival stratified by RV global longitudinal strain at presentation was analyzed.Seventeen patients with iPAH (mean age, 8.4 ± 4.8 years; seven male patients), of whom 11 were alive (group 1) and six had died or undergone transplantation (group 2), and 17 age-matched controls were studied. The median follow-up period was 1.5 years (range, 0.04-7.8 years). RV global longitudinal strain was significantly reduced in patients with iPAH compared with controls (-13.5 ± 5.9% vs -24.4 ± 3.9%, P .001) and in group 2 compared with group 1 at presentation (-9 ± 2.8% vs -16 ± 5.7%, P .05) and throughout follow-up. During follow-up, RV global and regional longitudinal strain worsened in group 2, especially in RV apical segments (-6.3 ± 5% vs -1.9 ± 1.6% at presentation compared with the last echocardiographic assessment in group 2, P .05), but was unchanged in group 1. RV global longitudinal strain-14% predicted transplantation-free survival with 100% sensitivity and 54.5% specificity.RV strain imaging may be useful for serial follow-up and prognostication in children with iPAH.

Background— Right ventricular diastolic dysfunction influences outcomes in pulmonary arterial hypertension (PAH), but echocardiographic parameters have not been investigated in relation to invasive reference standards in pediatric PAH. We investigated echocardiographic parameters of right ventricular diastolic function in children with PAH in relation to simultaneously measured invasive reference measures. Methods and Results— We prospectively recruited children undergoing a clinically indicated cardiac catheterization for evaluation of PAH and pulmonary vasoreactivity testing. Echocardiography was performed simultaneously with invasive reference measurements by high-fidelity micromanometer catheter. For analysis, patients were divided into shunt and nonshunt groups. Sixteen children were studied. In the group as a whole, significant correlations were found among τ and tricuspid deceleration time, E′ , E/E′ , Time E – E ′ , A wave velocity, and global early and late diastolic strain rate. d p /d t minimum correlated significantly with late diastolic tricuspid annular velocity ( A′ ), tissue Doppler imaging–derived systolic:diastolic duration ratio, and global late diastolic strain rate. End-diastolic pressure correlated significantly with tissue Doppler imaging–derived systolic:diastolic duration ratio. On multivariate analysis, tricuspid deceleration time, Time E – E ′ , and global early diastolic strain rate were independent predictors of τ, whereas tissue Doppler imaging–derived systolic:diastolic duration ratio was an independent predictor of d p /d t minimum. In general, correlations between echocardiographic and invasive parameters were better in the shunt group than in the nonshunt group. Conclusions— Echocardiography correlates with invasive reference measures of right ventricular diastolic function in children with PAH, although it does not differentiate between early versus late diastolic abnormalities. Newer echocardiographic techniques may have added value to assess right ventricular diastolic dysfunction in this population.

Background Matrix metalloproteinase (MMP)-9 is thought to be involved in coronary artery aneurysms (CAAs) in patients with Kawasaki disease (KD); however, MMP-9 inhibitors are not used clinically. This study investigated whether the angiotensin-converting enzyme (ACE) inhibitor captopril could inhibit serum MMP-9 activity using serum from KD patients in an in vitro experiment. Methods In 7 KD patients, serum MMP-9 activity was measured using the MMP-9 assay kit 3 times: before and after intravenous immunoglobulin (IVIG) treatment, and during the convalescent phase. The effect of captopril on MMP-9 activity was also assessed using serum obtained before IVIG treatment. Results Serum MMP-9 activity was significantly higher during the pre-treatment phase than during the post-treatment and convalescent phases. MMP-9 activity during the pre-treatment phase was dose-dependently inhibited by captopril, and the IC50 for MMP-9 was 500 nM. The potency of captopril for MMP-9 inhibition was comparable to that for ACE inhibition. Conclusion ACE inhibitor may be effective for preventing CAA formation in KD patients, especially IVIG non-responders.

Recently, many cases of children presenting reversible splenial lesions during febrile illness (RESLEF) have been reported; however, their overall clinico-radiological features are unclear. To describe the clinico-radiological features, we retrospectively reviewed the etiology (pathogen), clinical course, laboratory data, magnetic resonance imaging and electroencephalography (EEG) findings, therapy, and prognosis of 23 episodes in 22 children (1 child recurred) who presented neurological symptoms, with RESLEF. The etiologies (pathogens) varied. Seizure occurred in 7 episodes, disturbance of consciousness (DC) in 13, and delirious behavior in 18. Serum sodium levels

Objective: Establishing a new continuity between the right ventricle and the pulmonary artery is the mainstay of repair for persistent truncus arteriosus. We used the Tran Viet—Neveux technique without a Lecomte maneuver to construct the connection without a conduit. Here, we retrospectively review the mid-term surgical results to examinethe effectiveness of this approach. Methods:A cylindrical segment incorporating both pulmonary artery branches was sleeve-resected from the truncal artery. The cylindrical segment was cut in the middle and two truncal arterial flaps were combined to form the posterior floor of the new pulmonary arterial trunk. The edge of the floor was attached directly to the superior margin of an oblique incision made in the left-anterior wall of the right ventricle. A polytetrafluoroethylene monocusp was attached to the lower half margin of the right ventricular incision. A large glutaraldehyde-treated pericardial patch was used to form the anterior hood of the new right ventricular outflow tract. Both great arteries were located in a normal spiral configuration. Results: Ten babies (range: 3 days to 9 months of age) underwent this procedure.The Collett—Edwards classification of persistent truncus arteriosuswas type I in five cases and type II in five others. There was one hospital death due to severe respiratory distress. During follow-up (36—60 months, median 54 months), only one re- operation was required to enlarge a left branch pulmonary artery stenosis. Follow-up echocardiography showed pulmonary regurgitation (mild two, moderate seven, and severe one) and mild flow acceleration in the left pulmonary artery branch and right ventricle—pulmonary artery connection in one case. Conclusion: This simple modification for surgical correction of persistent truncus arteriosus may be an effective alternative that overcomes conduit-related problems. # 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

This study was performed to determine whether angiotensin (Ang) II-forming enzymes, angiotensin converting enzyme (ACE) and chymase might contribute to the development of adriamycin-induced cardiomyopathy in hamsters. Hamsters were administered adriamycin (2.0 mg/kg per day, i.p.) three times weekly for 2 weeks. In the ACE inhibitor-treated group, the hamsters received lisinopril (20 mg/kg per day, p.o.) for 2 weeks after the last injection of adriamycin. The 4-week mortality rates of the vehicle- and ACE inhibitor-treated hamsters were 44% and 12%, respectively. In comparison to the age-matched hamsters used as the control hamsters, a significant decrease in cardiac function and a significant increase in the ratio of the heart weight to the body weight were observed in the vehicle hamsters. Cardiac ACE activity, but not the chymase activity, in the vehicle hamsters was significantly increased in comparison to that in the control hamsters. In the ACE inhibitor-treated group, the increased ACE activity was reduced significantly, and the cardiac hypertrophy and dysfunction were improved significantly. In adriamycin-induced cardiomyopathic hamsters, cardiac ACE activity was increased and ACE inhibition significantly improved cardiac function and survival rate, indicating that cardiac ACE, but not the chymase, plays the pivotal role in the development of the adriamycin-induced cardiomyopathy.

We experienced two adult patients of Kawasaki disease with acute myocardial infarction who had not been pointed out coronary artery lesions previously. [Case 1: 27years old. Male] He suffered from Kawasaki disease at the age of one year. He did not receive any treatment of intravenous gamma-globulin therapy or aspirin. The cardiac catheterization at the age of 7 years revealed no coronary artery lesion. Thereafter, he had received follow-up examination once a year until 17 years old. He came to our outpatient clinic again because of recent recurrent chest pain at 22 years old. Further examinations including the cardiac catheterization, the treadmill test and the myocardial scintigraphy did not show any abnormalities and we concluded that his chest pain did not result from the coronary artery lesions of Kawasaki disease. After 5 years from these examinations, he suffered from an acute myocardial infarction with total occlusion of the right coronary artery (AHA Committee Report: Segment 2). He recovered well after the emergent percutaneus transluminal coronary anigioplasty (PTCA). [Case 2: 33 years old. Male] He suffered from Kawasaki disease at the age of two years. Any coronary artery lesion was not detected at that time. He had not received follow-up examinations since a few years after the onset. He had a chest pain at 30 years after the onset and had an acute myocardial infarction next year. The cardiac catheterization revealed 99% stenosis at segment 11, and total occlusion with well developed collaterals at segment 2. He recovered well after the directional coronary atherectomy (DCA) for the lesion at segment 11. [Conclusions] The patients with Kawasaki disease at the early era have grown to the young adult. They did not receive an accurate evaluation for the coronary artery lesions by echocardiography at the acute phase of Kawasaki disease. They did not receive effective therapy of gamma-globulin either. Those patients may have concealed coronary artery lesions. These two cases demonstrate well the high risk of those patients for the sudden onset of ischemic heart disease.

We experienced a case of Kawasaki disease with re-dilatation of coronary artery aneurysm five years after the onset. [Patient profile] The patient is a 12-year-old boy. He suffered from Kawasaki disease at the age of four years. Intravenous gamma-globulin (IVGG) therapy with 300 mg/kg/day was administered for 5 days, and additional IVGG with 1g/kg/day was administered furthermore. However, in spite of IVGG therapy, the aneurysms were developed on the both coronary arteries, which were confirmed by the cardiac catheterization one year later. (AHA Committee Report: Segment 2: two aneurysms; 4.8mm, 5.0mm in diameter, Segment 6: 4,3mm, Segment 11: 4.1mm). Thereafter, the coronary aneurysm on LAD regressed gradually. We depicted this regression of LAD aneurysm by the echocardiography at 4 years after the onset. (Segment 6: 2.4mm in diameter). However, further follow-up echocardiography revealed re-dilatation of the aneurysm on the same region of LAD one year later. (Segment 6: 7.4mm in diameter). We also confirmed this re-dilatation of the aneurysm without stenotic lesions by cardiac catheterization. [Discussion] There have been reported that the regressed aneurysms sometimes develop to the stenotic lesions late after the onset. However, there are a few reports in which a newly developed aneurysm emerged late after the onset of Kawasaki disease. [Conclusions] Re-dilatation of the regressed aneurysm is a very unique clinical course as a long-term Kawasaki disease. While the mechanism of the re-dilatation of this patient is still un-known, we must be careful to follow him up.